Kardassis Dimitris, Murphy Carol, Fotsis Theodore, Moustakas Aristidis, Stournaras Christos
Department of Biochemistry, University of Crete Medical School, Heraklion, Greece.
FEBS J. 2009 Jun;276(11):2947-65. doi: 10.1111/j.1742-4658.2009.07031.x. Epub 2009 Apr 23.
The integrated roles of small GTPases in executing the transforming growth factor beta (TGFbeta) signaling pathway have attracted increasing attention in recent years. In this review, we summarize recent findings on TGFbeta signaling during receptor endocytosis, Smad trafficking and actin cytoskeleton remodeling, and emphasize the role of small GTPases in these processes. First, we give an overview of the different endocytic routes taken by TGFbeta receptors, their impact on active TGFbeta signaling versus degradation and their regulation by the small GTPases Rab, RalA/Ral-binding protein 1 and Rap2. Second, we focus on the mechanisms and regulation of Smad trafficking in the cytoplasm, through the nuclear pores and into the nucleus, and the contribution of Ran GTPase to these events. Third, we summarize the role of Rho small GTPases in early and late cytoskeleton remodeling in various cell models and diseases, and the positive and negative cross-talk between Rho GTPases and the TGFbeta/Smad pathway. The biological significance of this exciting research field, the perspectives and critical open questions are discussed.
近年来，小GTP酶在执行转化生长因子β（TGFβ）信号通路中的综合作用受到了越来越多的关注。在本综述中，我们总结了受体胞吞作用、Smad转运和肌动蛋白细胞骨架重塑过程中TGFβ信号传导的最新发现，并强调了小GTP酶在这些过程中的作用。首先，我们概述了TGFβ受体所采用的不同胞吞途径、它们对活性TGFβ信号传导与降解的影响以及小GTP酶Rab、RalA/Ral结合蛋白1和Rap2对它们的调节。其次，我们关注Smad在细胞质中、通过核孔进入细胞核的转运机制和调节，以及Ran GTP酶对这些事件的贡献。第三，我们总结了Rho小GTP酶在各种细胞模型和疾病的早期和晚期细胞骨架重塑中的作用，以及Rho GTP酶与TGFβ/Smad通路之间的正负相互作用。讨论了这一令人兴奋的研究领域的生物学意义、前景和关键未解决问题。
